Novel synthetic approaches toward procyanidins and biflavonoids

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English: In this thesis we investigate procedures to introduce functional groups into the C-ring
of flavonoids. These include the introduction of a double bond, aryl coupling on the
C-3 position to obtain biflavonoids and aryl coupling on the C-4 position to obtain
proanthocyanidins.We observed that treatment of tetra-O-methyl-3-O-mesylcatechin with base yielded
the corresponding flav-3-ene. We optimized conditions to obtain yields close to 100%
(DBU, reflux in acetonitrile for 24 hours, mesyl derivative). Retention of
configuration at C-2 was observed. Treatment of tetra-O-methyl-3-O-tosylepicatechin
with DBU gives a mixture (ca 1:1 ratio) of the corresponding flav-2-ene and flav-3-
ene in high yield. The C-2 hydrogen of epicatechin is trans relative to the tosyl/mesyl
group at C-3 and base catalysed trans elimination to a flav-2-ene is feasible. This
contrasts with tetra-O-methyl-3-O-mesylcatechin where the C-2 hydrogen is cis
relative to the tosyl/mesyl group at C-3 and the only available trans hydrogen is at C-
4, resulting in the flav-3-ene exclusively. Flav-2-enes and flav-3-enes are normally
difficult to synthesize due to the ease with which they oxidize to anthocyanidins. We
have thus developed an efficient and high yielding method that yields the first
stereoselective access to optically active flav-3-enes. Treatment of tetra-O-methyl-3-oxocatechin with tri-O-methylphloroglucinol in the
presence of SnCl4 affords facile coupling of the phloroglucinol analogue at C-3 via a
carbon-carbon bond to give the 3-aryl-3,4-dehydrocatechin. The 3-arylcatechin
intermediate could not be isolated, presumably because water elimination is
encouraged by the formation of a stilbene-type conjugated system between the
electron rich A-and D-rings. CD data confirm retention of configuration at C-2. We
have thus developed proof of concept for the first stereoselective synthetic access to I-
3,II-6/8 biflavonoids. This represents a significant contribution towards flavonoid
synthesis. Treatment of tetra-O-methyl-3-oxocatechin with tri-O-methylphloroglucinol in the
presence of AgBF4 in THF afforded the C-4b- and C-4a phloroglucinol-3-oxocatehin adducts in 45% and 13% yields, respectively. Subsequent reduction with NaBH4 in
aqueous NaOH/MeOH afforded the C-4b and C-4a arylflavan-3-ol derivatives in
98% and 95% yields, respectively.The requirement of an excess of AgBF4 and the observation of a silver mirror
(reduction of Ag1 to Ag0) indicate a two-electron oxidative mechanism. No self
condensation or further condensation products were evident, probably due to the
deactivation of the nucleophilic properties of the A-ring of the 3-oxocatechin via the
enolic tautomer of the C-ring. The AgBF4-catalyzed condensation reaction between tetra-O-methyl-3-oxocatechin
and tetra-O-methylcatechin afforded the anticipated C-4b and C-4a dimers in 38%
and 6% yields, respectively, with [2R,4S (C-ring):2R,3S (F-ring)] and [2R,4R (Cring):
2R,3S (F-ring)] configurations, respectively, based on NMR coupling constants
and NOESY data. We thus developed a novel and facile method for the introduction of a phenolic unit at
unfunctionalized C-4 of per-O-methylcatechin and hence to synthesize procyanidin B-
3 type dimer derivatives. Our method has the following advantages:
1. It does not require pre-functionalization of the C-4 position of flavan-3-ols.
We have developed direct oxidative C-6/8 C-4 bond formation between two
flavonoid monomers. We could not find any previous usage of AgBF4 to
effect C-C bond formation. 2. Self condensation and the formation of homo-polymers are not observed. We
believe that the carbonyl group on the C-3 position of our one starting material
conjugates with the aromatic A-ring via its enol. This lowers the HOMO
energy and deactivates the A-ring to such an extent that it does not act as a
nucleophile. 3. The synthetic methods described so far rely on an electrophilic flavan-3-ol
with a hydroxy group at C-3. The configuration of the hydroxy group at C-3
controls the stereochemistry at C-4 and 3,4-trans proanthocyanidins are usually isolated as the major product. In our method, C-3 is a planar sp2
carbonyl and the stereochemistry at C-4 is controlled by the stereochemistry at
C-2 (configuration of the B-ring). We thus have access to both 3,4-cis and 3,4-
trans proanthocyanidins depending on the configuration of the B-ring at C-2. We have thus developed a unique and facile synthesis of catechin dimer derivatives
that circumvents the need for C-4 functionalization, avoids competing polymerization
and allows stepwise formation of hetero-oligomers. This method, based upon
oxidative C-C interflavanyl bond formation will contribute significantly to ready
synthetic access to proanthocyanidin analogues, especially procyanidins with 3,4-cis
congifured catechin chain extension units.